. The broad objective of this research proposal is to gain knowledge about the molecular mechanisms of thyroid physiology through the identification and characterization of human genetic errors causing defects of thyroid hormone regulation, synthesis, transport and action. Abnormal gene products will be characterized at the molecular level, and animal models will be generated for in-depth phenotype analysis. Five areas of study are proposed: (1) Subjects expressing the phenotype of thyrotropin resistance will be studied, in order to identify a putative thyrotropin-beta with reduced bioactivity, as well as thyrotropin receptor defects. The mechanism whereby in some families resistance to thyrotropin is inherited in an apparent dominant fashion, will also be included. (2) The sodium/iodide symporter will be sequenced in two families with iodide trapping defect and the nature of the functional defect will be characterized by in vitro expression. In addition, a genome-wide homozygosity screen will be used to identify the gene locus in a large Amish kindred with an apparent iodide organification defect. (3) The molecular basis of defects of thyroxine-binding globulin, transthyretin and albumin, will be identified and characterized. (4) The etiology of resistance to thyroid hormone in the absence of thyroid hormone receptor beta or alpha defects will be investigated, and the possibility of a defective corepressor or coactivator will be explored. In addition, a clinical protocol will be used to identify new families with thyroid hormone hypersensitivity and laboratory studies will be carried out to determine the molecular basis of this syndrome. (5) Finally, the role of genetic background on the variable clinical severity of the syndrome of thyroid hormone resistance will be explored, using mice strains with differing sensitivity to thyroid hormone. Somatic gene transfer of mutant thyroid hormone receptors will be performed, and the transgenic mice outbred to examine the effects on phenotypicexpression of the thyroid hormone resistance.